A major focus of work is the study of CNS opioid receptors. A goal of this work is to further define opioid receptor subtypes and develop new small molecules as research tools. Site-directed acylating agents selective for the kappa type of opioid receptor were developed, including UPHIT, which is active when administered intracerebroventricularly. Other studies examined the actions of site directed acylating agents selective for PCP receptors and sigma receptors. Several studies demonstrated the existence of multiple subtypes of kappa receptors, one of which may be associated with psychotic behavior in humans. Studies of the mechanism by which chronic naltrexone upregulates opioid receptors demonstrated that the irreversible mu antagonist, betafunaltrexamine, failed to prevent naltrexone-induced upregulation of the opioid receptor complex. Studies of morphine tolerance support the notion that the octapeptide, MMP-8, may play a major role in the development of tolerance and dependence to morphine. Two high affinity binding sites for EM were identified in guinea pig brain, the first associated with the receptor, and the second associated with the dopamine reuptake carrier. A strategy for identifying antagonists was developed, and GBR12909 was identified as a putative cocaine antagonist.